6-thiocyanato-16-methylene-4,6-pregnadienes, methods for their manufacture, and intermediates there of

ABSTRACT

6-Thiocyanato-16-methylene-17 Alpha -lower alkanoyloxy-4,6pregnadiene-3,20-diones having progestational and anti-androgenic activities are prepared from 6 Beta -thiocyanato-7 Alpha hydroxy-16-methylene-17 Alpha -lower alkanoyloxy-4-pregnene-3,20diones by treatment in a tertiary amine with a hydrocarbonsulfonyl halide having up to seven carbon atoms. The 6-thiocyanato-16-methylene-4,6-pregnadienes of this invention are also prepared by treating a 6 Beta -thiocyanato-7 Alpha -hydroxy16-methylene-17 Alpha -lower alkanoyloxy-4-pregnene-3,20-dione or a 7-lower alkanoate ester thereof with an acid selected from the group consisting of p-toluenesulfonic acid or hydrochloric acid in a non-reactive, organic solvent.

United States Patent Shapiro [5 6-TH1OCYANATO-16-METHYLENE-4,6- PREGNADIENES, IVETHQDS FOR THEIR MANUFACTURE, AND INTERMEDKATES TEERE OF Elliot L. Shapiro, Cedar Grove, NJ.

Assignee: Schering Corporation, Bloomfield, NJ.

Filed: March 31, 1971 Appl. No.: 129,949

Int. Cl ..C07c 169/32 Field of Search Machine Searched Steroids [5 6] References Cited UNITED STATES PATENTS 3,407,217 10/1968 Hughes et al. ..260/397.4

Primary Examiner-Elbert L. Roberts Attorney-Stephen B. Coan and Mary S. King [57] ABSTRACT 6-Thiocyanato-1 -methylene- 1 7a-lower alkanoyloxy-4,6- pregnadiene-3,20-diones having progestational and anti-androgenic activities are prepared from 6B-thiocyanato-7ahydroxy- 1 6-methy1enel 7a-lower alkanoyloxy-4-pregnene- 3,20-diones by treatment in a tertiary amine with a hydrocarbonsulfonyl halide having up to seven carbon atoms. The 6- thiocyanato-l6-methylene-4,-pregnadienes of this invention are also prepared by treating a 6B-thi0cyanato-7a-hydroxyl6-methylenel 7a-lower alkanoyloxy-4-pregnene-3 ,20-dione or a 7-lower alkanoate ester thereof with an acid selected from the group consisting of p-toluenesulfonic acid or hydrochloric acid in a non-reactive, organic solvent.

1 1 Claims, No Drawings FIELD OF INVENTION This invention relates to novel compositions of matter, to methods for their manufacture, and to novel intermediates useful therein.

More specifically, this invention relates to novel 6-thiol SUMMARY OF INVENTION The invention sought to be patented in a composition-ofmatter aspect resides in the concept of a chemical compound having progestational and anti-androgenic activity which has a molecular structure comprising a 4,6-pregnadiene-3,20-dione nucleus with a thiocyanato group at C-6, a methylene group at C-l6 and an a-lower alkanoyloxy group at Cl7.The preferred compound is that having a l7a-acetoxy group.

The invention sought to be patented in another composition-of-matter aspect resides in the concept of a chemical compound useful as an intermediate which has a molecular structure comprising a 4-pregnene-3,20-dione nucleus with a a-thiocyanato group at C.6, an d-hydroxy group or a lower alkanoate ester thereof at C-7, a methylene group atC-16, and an a-lower alkanoyloxy group at C-17.

The invention sought to be patented in a process aspect of this invention resides in the concept of treating a 6B-thiocyanato-7a-hydroxy-1 6-methylenel 7a-lower alkanoyloxy-4- pregnene-3,20-dione in a tertiary amine with a hydrocarbonsulfonyl halide' having up to seven carbon atoms whereby is produced a 6-thiocyanato-4,6-pregnadiene-3,20-dione of this invention having progestational and anti-androgenic activity. A preferred species of this process aspect is that wherein the tertiary amine is pyridine and the hydrocarbonsulfonyl halide is methanesulfonyl chloride.

The invention sought to be patented in another process aspect of this invention resides in the concept of treating a member selected from the group consisting of a 6B-thiocyanato-7a-hydroxyl 6-methylenel 7a-lower alkanoyloxy-4- pregnene-3,20-dione and a 7-lower alkanoate ester thereof with an acid reagent selected from the group consisting of p toluenesulfonic acid and hydrochloric acid in an inert solvent.

GENERAL DESCRIPTION OF THE INVENTION COMPOSITION-OF-MA'ITER ASPECT Included among the physical embodiments of the progestationally active composition-of-matter aspect of this invention are 6-thiocyanatol 6-methylenel 7a-l0wer alkanoyloxy-4,6- pregnadiene-Ii,20-diones having the following structural Formula I:

r (1:0 CH3 l CH2 OH. I /\l/ k/ SON 1 wherein Y is lower alkanoyloxy.

The lower alkanoyloxy groups are preferably derived from lower alkanoic acids having up to eight carbon atoms including acetic, propionic, n-butyric, iso-butyric, tri-methyl acetic, valeric, iso-valeric, caproic, and caprylic acid.

Included among the l7a-lower alkanoyloxy compounds of this invention are: -thiocyanatol 6-methylenel 7a-acetoxy-4,6-pregnadiene- 3,20-dione (preferred compound of this invention), -thiocyanatol 6-methylenel 7a-propionyloxy-4,6- pregnadiene-3,20-dione, 6-thiocyanatol 6-methylene- 1 7avaleryloxy-4,6-pregnadiene-3 ,20-dione, and o-thiocyanatol 6-methylenel 7a-caproyloxy-4,6- pregnadiene-3,20-dione.

The physical embodiments of the 6-thiocyanato-6- dehydroprogesterones of Formula I are characterized by being crystalline solids usually off-white to white in color which are insoluble in water and soluble in most organic solvents, although of limited solubility in dialkyl esters and aliphatic hydrocarbons.

The -thiocyanatol 6-methylenel 70z-lower alkanoyloxy-6- dehydroprogesterones defined by Formula I may be used as a medicament in conditions requiring a progestational agent, e.g. fertility control and in the management of various menstrual disorders. Also, in the veterinary field, the compounds of Formula I may be used to establish estrus synchronization of large farm animals, eg the cow and the sheep, making these compounds of particular use when breeding farm animals. These compounds may be administered via the intramuscular route in amanner similar to that in which known progestational agents, e.g. progesterone, are administered, the dosage depending on the age and size of animal or patient and on the nature and severity of the illness being treated. The progestational activity of compounds of Formula I is demonstrated by studies in the rabbit via the intramuscular route by the well known Clauberg method. For example, in this test, 6- thiocyanato-l6-methylene-1 7a-acetoxy -4,6-pregnadiene- 3,20-dione is about 12 times as active as progesterone via the intramuscular route.

The compounds of Formula I are also useful in the treatment of disorders requiring anti-androgen therapy such as in the treatment of acne or benign prostatic hypertrophy. The

' anti-androgen activity of compounds of Formula I is studied in the intact male immature rat by the test described by RC.

. Neri, et al. Eur. J. Pharm. 1, 438444 (1967) (Section 2.1.2,

page 439). It was demonstrated, for example, that at doses as low as l mgm./kgm. administered subcutaneously in sesame oil, anti-androgenic activity was exhibited by the preferred compound of this invention, i.e. 6-thiocyanatol G-methylenel 7-a-acetoxy4,6-pregnadiene-3,20-dione.

GENERAL DESCRIPTION OF 6BTHIOCYANATO-7a- OXYGENATED PROGESTERONE INTERMEDIATES OF THE INVENTION II wherein R is a member s elected from the group consisting of hydrogen and lower alkanoyl and Y is lower alkanoyloxy.

Typical intermediates of Formula II include compounds such as 6B-thioeyanato-7a-hydroxy-l6-methylene-l7aacetoxy progesterone (i.e. 6B-thiocyanato-7a-hydroxy-l6- methylene-l7a-acetoxy -4-pregnene-3,20-dione, a preferred intermediate of this invention), and the 7-acetate ester thereof, 6B-thiocyanato-7a-hydroxyl -methylenel 7a-propionyloxy- 4-pregnene-3,20-dione and the 7a-acetate ester thereof, 6fl-thiocyanato-7a-hydroxyl 6-methylenel 7a-valeryloxy-4- pregnene-3,20-dione and the 7a-acetate and 7a-valerate esters thereof, and 6B4hiocyanato-7a-hydroxy-1 6-methylenel 7a-caproyloxy-4- -pregnene-3,20-dione and the 7a-acetate, 7oz-propionate and 7a-caproate esters thereof.

The physical embodiments of the compounds defined by Formula II are characterized by being crystalline solids, usually off-white to white in color, and soluble in chlorinated hydrocarbons, acetone, and lower alkyl alcohols, e.g. methanol.

The 6B-thiocyanato-7a-hydroxy-4-pregnene-3,20-diones of Formula II are conveniently derived from the corresponding 60:, 7a-oxido derivatives which in turn are prepared by known procedures from 1 6-methylenel 7a-hydroxy-4,6- pregnadiene-3,20-dione by esterification thereof such as with a lower alkanoic acid together with trifluoracetic anhydride and p-toluenesulfonic acid to produced the corresponding 6a, 7a-0Xidol 7-lower alkanoyloxy-4,6-pregnadiene-3,20-dione followed by epoxidation of the 6,7-double bond by means of peracids such as perphthalic acid whereby is produced the desired 6a, 7a-oxido-l7a-lower alkanoyloxy-4-pregnene- 3,20-dione. Thus, for example, esterification of l6-methylene- 17a-hydroxy-4,6-pregnadiene-3,20-dione with a reagent mixture comprising acetic acid and trifluoroacetic anhydride and p-toluene sulfonic acid yields l6-methylene-l7a-acetoxy-4,6- pregnadiene-3,20-dione which upon treatment with perphthalic acid according to known procedures yields 6a, 7a-oxidol o-methylene- 1 7a-acetoxy-4-pregnene-3 ,20-dione. The 60:, 7a-oxido intermediate is the converted to a compound of Formula II by treatment with an alkali metal thiocyanate (e.g, potassium thiocyanate) in a non-reactive, or-

ganic solvent, preferably a lower alkanol in which acetic acid and water is present e.g. aqueous methanol in the presence of acetic acid) under mild conditions utilizing techniques known in the art to obtain the 6B-thiocyanato-7a-hydroxy-4- pregnene-3,20-diones of Formula II. Thus, for example, 60:, 7a-oxidol 6-methylenel 7a-acetoxy-4-pregnene-3 ,20-dione treated with potassium thiocyanate in aqueous methanol in the presence of acetic acid at room temperature for 48 hours is converted to ofl-thiocyanato-7a-hydroxy-l6-methylene-l7 a-acetoxy-4-pregnene-3,20-dione.

The compounds of Formula I] wherein R is lower alkanoyl are derived from the corresponding compounds of Formula II wherein R is hydrogen by utilizing standard esterification techniques under basic conditions such as that of utilizing acetic anhydride in pyridine. Thus, treatment of the aforedescribed 6/3-thiocyanato-7a-hydroxyl 6-methylenel 7 a-acetoxy-4-pregnene-3,20-dione (a compound of Formula II wherein R is hydrogen) with acetic anhydride in pyridine at room temperature yields 6B-thiocyanato-7a, l7a-diacetoxi acetoxy-l6-methylene-4-pregnene-3,ZO-dione (a compound of Formula II wherein R is acetyl).

PROCESS ASPECTS OF THE INVENTION The process aspect of this invention provides a method for preparing the pharmacologically active 6-thiocyanato-l6- methylene-l7a-lower alkanoyloxy-4,-pregnadienes of Formula I and resides in the concept of treating a corresponding 6B-thiocyanato-7a-hydroxyl 6-methylene- 1 7a-lower alkanoyloxy-4,6-pregnadiene-3,20dione of Formula II with a hydrocarbonsulfonyl halide having up to seven carbon atoms in a tertiary amine.

Tertiary amines useful as solvents in this reaction include 2- methylpyridine, triethylamine, and preferably pyridine.

Hydrocarbonsulfonyl halides contemplated for use in this process include acylbromide and acylchloride derivatives of benzenesulfonic acid, methanesulfonic acid and p-toluenesulfonic acid. Preferred are the hydrocarbonsulfonyl chlorides, particularly p-toluenesulfonyl chloride and methanesulfonyl chloride.

A preferred species of this process aspect is that utilizing a hydrocarbonsulfonyl chloride (usually p-toluenesulfonyl chloride or, preferably methanesulfonyl chloride) in tertiary amine (preferably pyridine). This preferred method is of particular value when carried out on a 6 B-thiocyanato-7ahydroxy- 1 6-methylenel 7a-acetoxy-4-pregnene-3,20-dione whereby is prepared a preferred compound of this invention, i.e. 6-thio cyanatol 6-methylene-l 7a-acetoxy-4,6- pregnadiene-3,20-dione The physical embodiment of the preferred method of this process is usually carried out by suspending or dissolving a 6B- thiocyanato-7a-hydroxyl 6-methylene-l 7a-lower alkanoyloxy progesterone e.g. 6B-thiocyanato-7a-hydroxy-l6- methylene-l7B-acetoxyprogesterone) in pyridine, adding a hydrocarbonsulfonyl chloride (e.g. methanesulfonyl chloride) (2 moles sulfonyl chloride per mole of steroid usually being employed), and allowing the reaction mixture to remain at temperatures in the range of from about 0 C to about 40 C (preferably at ambient temperatures) for about 20 hours or until a thin layer chromatogram of an aliquot of the reaction mixture indicates an absence of 6B-thiocyanato-7a-hydroxy starting compound. The resulting 6-thiocyanato-l6- methylenel 7a-lower alkanoyloxy-6-dehydroprogesterone e. g. 6-thiocyanatol 6-methylenel 7a-acetoxy-4,6- pregnadiene-3,20-dione) is then easily isolated by pouring the reaction mixture into ice water, stirring until the insoluble fraction separates as a solid, collecting the insoluble fraction by filtration or extraction, and purifying using known methods such as crystallization or via chromatographic techniques.

The necessary 6/3-thiocyanato-7a-hydroxyprogesterone intermediates for this process (e.g. GB-thiocyanato-7a-hydroxyl 6-methylenel 7a-acetoxy-4-pregnene-3 ,20dione) are novel compounds of Formula II which are prepared from the corresponding 6a, 7a-oxido derivatives (known in the art) as described hereinabove. When carrying out the preferred method of this process, I have found it most convenient to prepare the preferred intermediate by reacting 6a, 7a-oxidol6-methylene-l7a-acetoxy progesterone with potassium thiocyanate in aqueous methanol in the presence of acetic acid.

In another process aspect of this invention, there is provided another method for preparing the pharmacologically active 6- thiocyanatol 6-methylenel 7a-lower alkanoyloxy-4,6- pregnadiene-3,20-diones of Formula I and resides in the concept of treating a member selected from the group consisting of a 6B-thiocyanato-7a-hydroxy-l6-methylene-l7a-lower alkanoyloxy progesterone and a 6B-thiocyanato-7a-hydroxyl6-methylene-l7a-lower alkanoyloxy progesterone and a 6,8- thiocyanato-l7-bis-lower alkanoyloxy- 16- methyleneprogesterone with an acid such as hydrochloric acid or p-toluenesulfonic acid in a non-reactive, organic solvent.

When carrying out the physical embodiment of this process aspect, by non-reactive, organic solvent" is contemplated an organic solvent in which the 6a-thiocyanato-7a-hydroxy steroid intermediate or 7a-lower alkanoate thereof and the acid reagent are soluble, as well as a solvent, which will not react with the acid or steroid substrate under the conditions of the reaction so as to cause transformations which will result in the occurrence of competing side reactions. Included among the non-reactive, organic solvents contemplated when an acid such as p-toluene sulfonic acid or hydrochloric acid are used as dehydrating agents are halogenated hydrocarbons including methylene chloride, carbon tetrachloride and, preferably, chloroform; acetone; aqueous dioxane; lower alkanoic acids, preferably acetic acid; and solvent mixtures such as lower alkanoic acids (e.g. acetic acid) and acetone.

The hydrochloric acid employed in this process may be anhydrous hydrogen chloride or may be aqueous hydrochloric acid of which concentrated hydrochloric acid is preferred.

When anhydrous hydrogen chloride is employed, preferred solvents are halogenated hydrocarbons, particularly chloroform. When concentrated aqueous hydrochloric acid is used as dehydrating agent, included among the non-reactive, organic solvents which are conveniently employed are acetone or aqueous dioxane.

The 6B-thiocyanato-7a-hydroxyl 6-methylenel 7a-lower alkanoyloxyprogesterones and 6fl-thiocyanato-7a, l7a-dilower alkanoyloxy-l6-methyleneprogesterones, necessary intermediates in this process, are novel compounds of Formula ll described hereinabove.

The physical embodiment of this process aspect of my invention is usually carried out by dissolving or suspending a 6B- thiocyanato-7a-hydroxyprogesterone or 7a-lower alkanoate thereof e. g., 6B-thiocyanato-7a-hydroxy-l6-methylene-17aacetoxy-4-pregnene-3,20-dione or 711, l7a-di-acetoXy-l6- methylene-4-pregnene-3,20-dione) in a large volume of solvent (e.g. preferably chloroform in ratios of about 1 part steroid to 100 parts chloroform) and adding the acid reagent (e.g. preferably p-toluenesulfonic acid) in amounts comprising about 0.25 moles acid per mole steroid, and allowing the reaction mixture to remain at temperatures in the range of from about C to about 40 C (preferably ambient temperatures) for about 3 days or until a thin layer chromatogram of an aliquot of the reaction mixture indicates the absence of 6,8- thiocyanato-7a-hydroxyprogesterone or of 6B-thiocyanato-7 ot-lower alkanoyloxyprogesterone starting steroid. The resulting 6-thiocyanato-4,6-pregnadiene (e.g. 6-thiocyanato-l'6- methylene-17a-acetoxy-4,6-pregnadiene- 3,20-dione) is then conveniently isolated via separation of products on preparative thin layerchromatographic plates utilizing procedures known in the art.

My invention is further described in the following examples which are set forth for illustrative purposes only. It will be understood the invention is not to be construed as limited in scope by the details set forth therein, since modifications and equivalents both in materials and methods will be apparent from the disclosure to those skilled in the art.

EXAMPLE 1 6-thiocyanatol 6-methylenel 7a-acetoxy-4,-pregnadiene- 3 ,20-dione (-thiocyanatol -methylenel 7a-acetoxy-6- dehydroprogesterone) A. fl-Thiocyanato-Ta-hydroxyl o-methylenel 7a-acetoxy-4- pregnene-3,20-dione (6fl-thiocyanatoJa-hydroxy-l6- methylenel 7-acetoxyprogesterone) To a solution of l g. of 6a, 7a-oxido-l6-methylene-l7aacetoxy-4-pregnene-3,20-dione in 160 ml. of methanol, add a solution of 6 g. of potassium thiocyanate in 40 ml. of water and 1 ml. of acetic acid. Allow the reaction mixture to remain at room temperature for 48 hours, then pour the reaction mixture into 800 ml. of water, extract the aqueous reaction mixture with chloroform, and dry the combined chloroform extracts over magnesium sulfate. Distill the chloroform solution in vacuo to a residue comprising 6B-thiocyanato-7a-hydroxyl6-methylenel 7a-acetoxy-4-pregnene-3,20-dione. Purify the residue by crystallization from ethyl acetate to obtain 882 mg. (77percent theoretical yield) of 6B-thiocyanato-7a-hydroxyl o-methylenel 7a-acetoxy-4-pregnene-3 ,ZO-dione, [a] 23.0 (dioxane); AZIZT 241 p. (e=l3,637).

B. G-Thiocyanatol 6-methylenel 7a-acetoxy-4,6- pregnadiene-3,20-dione Add 40 drops of methanesulfonyl chloride to a solution of 700 mg. of 6,8-thiocyanato-7a-hydroxy-l 6-methylene-17aacetoxy-4-pregnene-3,20-dione in 20 ml. of pyridine cooled in an ice bath. Allow the reaction mixture to remain at room temperature for 20 hours, then pour into 150 ml. of ice water. Stir for 30 minutes, then collect the resulting precipitate by filtration and dry the precipitate to obtain 616 mg. of solid comprising 6-thiocyanatol -methylenel 7a-acetoxy-4,6- pregnadiene-3,20-dione, [04],, l 22.5 (dioxane).

EXAMPLE 2 Alternate Procedure for Preparing -Thiocyanato l 6- methylenel 7a-acetoxy-4,6-pregnadiene-3 ,20-dione A. 6B-Thiocyanato-7a, pregnene-3,20-dione Add 0.5 ml. of acetic anhydride to an ice-cooled solution of 574 mgm. of 6B-thiocyanato-7a-hydroxy-l6-methylene-l7aacetoxy-4-pregnene-3,20-dione in 8 ml. of pyridine. Allow the reaction mixture to remain at room temperature for 6 hours, then at 5 C add 2 ml. additional acetic anhydride and allow the reaction mixture to stand at 5 C for 24 hours. Pour the reaction mixture into water, collect the resultant precipitate by filtration, wash the precipitate with water, then with cold methanol. Dry the precipitate at room temperature in vacuo to obtain 480 mg. of a solid comprising 6B-thi0cyanato-7a, l7a-di-acetoxyl 6-methylene-4-pregnene-3,20-dione which is used without further purification in following step B. B. 6-Thiocyanatol 6-methylenel 7a-acetoxy-4,6- pregnadiene-3,20-dione To a solution of 50 mg. of 6B-thiocyanat0-7a, l7a-diacetoxy-l6-methylene-4-pregnene-3,20-dione in 5 ml. of chloroform, add 12 mg. of p-toluenesulfonic acid. Allow the reaction mixture to remain at room temperature for 3 days. Add water to the reaction mixture and discard the aqueous phase. Wash the organic solution with aqueous sodium bicarbonate, then with water. Dry the chloroform solution over magnesium sulfate, then evaporate to a residue comprising 6- thiocyanato- 1 o-methylenel 7aacetoxy-4,6-pregnadiene-3 ,20 dione. Purify by preparative thin layer chromatography on silica gel utilizing as developing solvent a mixture of chlorofonn-ethylacetate (9:1 Yield 28 mgm.

1 7a-di-acetoxyl 6-methylene-4- EXAMPLE 3 Other -Thiocyanatol 6-methylene- 1 7a-Iower alkanoyloxy- 4,6-pregnadiene-3,20-diones A. 6/3-Thiocyanato-7a-hydroxy-l6-methylene-l7a-lower alkanoyloxy 4-pregnene-3,20-dione In a manner similar to that described in Example lA, treat each of the following with potassium thiocyanate in aqueous methanol and in the presence of acetic acid: 60:, 3 ,ZO-dione, 6a, 7a-oxidol 6-methylenel 7a-n-butyryloxy-4- pregnene-3,20-dione, and 6a, 7a-oxidol 6-methylene- 1 7a-valeryloxy-4-pregnene-3 ,20-

dione. Isolate and purify the resultant productsin a manner similar to that described in Example 1A to obtain, respectively, 6/3-thiocyanato-7a-hydroxyl 6-methylenel 7a-propionyloxy- 4-pregnene-3,20-dione, 6B-thiocyanato-7a-hydroxyl 6-methylenel 7a-n-butyryloxy- 4-pregnene-3 ,20-dione, and 6B-thiocyanato-7a-hydroxy- 1 6-methylenel 7avaleryloxy-4- pregnene-3,20-dione. B. 6-Thiocyanato-l6-methylene-l7a-lower alkanoyloxy-4,6- pregnadiene-3,20-dione In a manner similar to that described in Example 18, treat each of the 6B-thiocyanato-7a-hydroxyl o-methylene-l lower alkanoyloxyprogesterones prepared in Example 3A with methanesulfonyl chloride in pyridine. Isolate and purify each of the resultant products in a manner similar to that described in Example IE to obtain, respectively, 6-thiocyanatol 6-methylene- 1 7a-propionyloxy-4,6- pregnadiene-3,20-dione, 6-thiocyanatol 6-methylenel 7a-n-butyryloxy-4,6- pregnadiene-3 ,20-dione, and 6B-thiocyanatol 6-methylenel 7a-valeryloxy-4,6- pregnadiene-3,20-dione. Alternatively, the compounds of this invention are prepared according to following procedures C, D and E.

7a-oxidol o-methylene- 1 7a-propionyloxy-4-pregne ne- In a manner similar to that described in Example 2A, treat each of the fi-thiocyanato-7a-hydroxy-l6-methylene-17alower alkanoyloxy-4-pregnene-3,20-diones prepared in Example 2A with acetic anhydride in pyridine. Isolate and purify each of the resultant products in a manner similar to that described in Example 2A, to obtain, respectively, fl-thiocyanato-7a-acet0xyl -methylenel 7a-propionyloxy- 4-pregnene-3,20-dione,

6,8-thiocyanato-7a-acetoxyl -methylenel 7a-n-butyryloxy- 4-pregnene-3,20-dione, and 6/3-thiocyanato-7a-acetoxyl 6-methylenel 7a-valeryloxy-4- pregnene-3,20-dione.

In the above procedure, by utilizing anhydrides of other lower alkanoic acid instead of acetic acid, such as propionic anhydride and n-butyric anhydride, there is obtained the corresponding 7a-lower alkanoate ester, e.g. the corresponding 7a-pr0pionyloxy and 7a-butyryloxy esters of the 6/3-thiocyanato-7a-hydroxyl -methylenel 7a-lower alkanoyloxyprogesterone starting compounds. D. -Thiocyanato-l 6-methylenel 7a-lower alkanoyloxy-4,6- pregnadiene-3,20-dione In a manner similar to that described in Example 2B, treat each of the fl-thiocyanato-7a-acetoxy-l-methylene-l7alower alkanoyloxy-4-pregnene-3,20-diones prepared in Example 3C with p-toluenesulfonic acid in chloroform. Isolate and purify each of the resultant products in a manner similar to that described in Example 28 to obtain, respectively,

6-thiocyanato-l6-methylene-1 7a-propionyloxy-4,6- pregnadiene-3 ,20-dione,

6-thiocyanatol -methylenel 7a-n-butyryloxy-4,6- pregnadiene-B,20-dione, and

-thiocyanatol 6-methylenel 7a-valeryloxy-4,6- pregnadiene-3,20-dione.

In the above procedure, in place of the 6,8-thiocyanato-7aacetoxyl G-methylenel 7a-lower alkanoyloxy-4-pregnene- 3,20-dione intermediates employed therein there may be utilized the corresponding 7a-propionyloxy or 7a-n-butyryloxy ester analogs thereof and there will be obtained the corresponding 6-thiocyanatol 7a-lower alkanoyloxy-4,6- pregnadiene. For example, by treating 6B-thiocyanato-7a, l7a-propionyloxyl 6-methylene-4-pregnene-3,20-dione with p-toluenesulfonic acid in chloroform in the manner of Example 28, there is obtained 6-thiocyanato-l6-methylene-l7apropionyloxy-4,6-pregnadiene-3,20-dione.

I claim:

1. A compound having the following structural formula:

wherein Y is lower alkanoyloxy.

2. A compound according to claim 1 wherein Y is acetoxy, said compound being 6-thi0cyanat0-l6-methylene-l7aacetoxy-4,6-pregnadiene-3,20-dione.

3. A compound having the following structural formula:

diacetoxyl 6-methylene-4-pregnene-3 ,20-dione.

6. A process for preparing -thiocyanato-l6-methylene-l7 a-lower a1kanoyloxy-4,6-pregnadiene-3,20-diones of the following Formula I:

S C N I wherein Y is lower alkanoyloxy; which comprises treating a 6,8-thiocyanato-7a-hydroxy-4-pregnene-3,20-dione of following Formula A:

wherein Y is lower alkanoyl;

with a hydrocarbonsulfonyl chloride having up to seven carbon atoms in a tertiary amine.

7. A process according to claim 6 wherein said tertiary amine is pyridine.

8. A process according to claim 6 wherein said hydrocarbonsulfonylchloride is methanesulfonyl chloride, said tertiary amine is pyridine, and said 6B-thiocyanato-4-pregnene-3,20- dione is an intermediate of Formula A wherein Y is acetoxy, said process comprising treating 6,8-thiocyanato-7a-hydroxyl 6-methylenel 7a-acetoxy-4-pregnene-3,20-dione with methanesulfonyl chloride in pyridine to obtain 6-thiocyanat0- 1 6-methylenel 7a-lower alkanoyloxy-4,-pregnadiene-3 ,20- dione.

9.' The process for preparing 6-thiocyanato-l6-methylenel7a-lower alkanoyloxy-4,6-pregnadiene-3,ZO-dione which comprises treating 6aa-oxido-l6-methylene-l7a-lower alkanoyloxy-4-pregnene-3,20-dione with an alkali metal thiocyanate in the presence of a lower alkanoic acid and in a nonreactive, organic solvent, and treating the resulting GB-thiocyanato-7a-hydroxyl -methylene- 1 7a-lower alkanoyloxy-4- pregnene-3,20-dione in pyridine with a hydrocarbonsulfonyl chloride having up to seven carbon atoms.

10. The process according to claim 9 wherein said 1704- lower alkanoyloxy is acetoxy, said metal thiocyanate in the presence of a lower alkanoic acid and in a non-reactive, organic solvent is potassium thiocyanate in aqueous methanol in the presence of acetic acid, and wherein said hydrocarbonsulfonyl chloride is methanesulfonyl chloride, said process comprising treating 6a,7a-oxido-l6-methylene-l7a-acetoxy-4- pregnene-3,20-dione with potassium thiocyanate in aqueous methanol in the presence of acetic acid, and treating the thereby formed 6/3-thiocyanato-7a-hydroxy-l6-methylene-17 a-acetoxy-4-pregnene-3,20-dione with methanesulfonyl chloride in pyridine whereby is obtained 6-thiocyanato-l6- methylenel 7a-acetoxy-4,-pregnadiene-3,20-dione.

11 A process for preparing 6-thiocyanato-l6-methylene-17 a-lower alkanoyloxy-4,6-pregnadiene-3,20-diones of the following Formula 1:

CII: i CH W YCHz CH /V wherein Y is lower alkanoyloi y;

which comprises treating a 6/3- thiocyanato-7a-oxygenated- 4-pregnene-3 ,20-dione of following Formula A:

Patent No. 5 75 5 Dated June 27, 1972 Inventor(s) Shapiro It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 50, -thiocyanato" should read --B-thiocyanato---. Column 5 line 58, "is the converted" should read ---is then converted--. Column 5, line :5, "present e. g. aqueous" should read --prese'nt (e. 5;. aqueous---. Column 5 lines 60 and 61 "-7 ,l7 -diacetoxy acetoxy-" should read ----T ,l'T cliacetoxy---. Column line 1 "6-thio cyanato" should read --6 i;hiocyanato---. Column lines 19 and 20, "progesterone e. g.

ifi-thiocyanatoT hydroxy-l6.-methylene-l7B-" should read progesterone (e. g. 6f -chiocyanaco-7 -hydroxy-l6 -methylenelT Column h, line 59, "5,-2odione" should read ---5,2O-di'one-. Column lines '55 -56, "and a; 6f -fbhiocyana'bo-'T -hydroxyl6- methylene-l'W-lower alkanoyloxy progesterone and a 6f -thiocyanatol'T-bis-lower alkanoyloxy-l6-methylene-progesterone with an acid such ashydrochloric acid" should read --and a 65-thiocyanato- Whl'W-bis-lower alkanoyloxy-l6-methylene-progesterone with an aci such as hydrochloric acid--. Column line 60, v "6 -thioc anato" should read ---6i -thiocyanato '-w Column 5, line 6h, me hanOl max thanol 2m n" should read 2&1. I a". Column 6, line 57,

dflvaleryloxy should read ----lT *valeryloxy---'-. Column 7, line 6?, Claim 1 in the formula, at C-6 and C-7 of Ring B,

4kg?! should appear M CN SCN Column 8, line T5, Claim 9,"6 -o'xido"should read ---6 ,T oxido---. Column 9, line 29, Claim 11 in formula I at 0-6 and (3-7 of Ring 13, y,\/ should appear f? Signed and sealed this 5rd day of April 1-973.

EDWARDMPLETCHERJR. ROBERT GOTTSCHALK Attestlng Officer Commissioner of Patents 

2. A compound according to claim 1 wherein Y is acetoxy, said compound being 6-thiocyanato-16-methylene-17 Alpha -acetoxy-4,6-pregnadiene-3,20-dione.
 3. A compound having the following structural formula:
 4. A compound according to claim 3 wherein R is hydrogen and Y is acetoxy, said compound being 6 Beta -thiocyanato-7 Alpha -hydroxy-16-methylene-17 Alpha -acetoxy-4-pregnene-3,20-dione.
 5. A compound according to claim 3 wherein R is acetyl and Y is acetoxy, said compound being 6 Beta -thiocyanato-7 Alpha ,17 Alpha -diacetoxy-16-methylene-4-pregnene-3,20-dione.
 6. A process for preparing 6-thiocyanato-16-methylene-17 Alpha -lower alkanoyloxy-4,6-pregnadiene-3,20-diones of the following Formula I:
 7. A process according to claim 6 wherein said tertiary amine is pyridine.
 8. A process according to claim 6 wherein said hydrocarbonsulfonylchloride is methanesulfonyl chloride, said tertiary amine is pyridine, and said 6 Beta -thiocyanato-4-pregnene-3,20-dione is an intermediate of Formula A wherein Y is acetoxy, said process comprising treating 6 Beta -thiocyanato-7 Alpha -hydroxy-16-methylene-17 Alpha -acetoxy-4-pregnene-3,20-dione with methanesulfonyl chloride in pyridine to obtain 6-thiocyanato-16-methylene-17 Alpha -lower alkanoyloxy-4,6-pregnadiene-3,20-dione.
 9. The process for preparing 6-thiocyanato-16-methylene-17 Alpha -lower alkanoyloxy-4,6-pregnadiene-3,20-dione which comprises treating 6-oxido-16-methylene-17 Alpha -lower alkanoyloxy-4-pregnene-3,20-dione with an alkali metal thiocyanate in the presence of a lower alkanoic acid and in a non-reactive, organic solvent, and treating the resulting 6 Beta -thiocyanato-7 Alpha -hydroxy-16-methyleNe-17 Alpha -lower alkanoyloxy-4-pregnene-3,20-dione in pyridine with a hydrocarbonsulfonyl chloride having up to seven carbon atoms.
 10. The process according to claim 9 wherein said 17 Alpha -lower alkanoyloxy is acetoxy, said metal thiocyanate in the presence of a lower alkanoic acid and in a non-reactive, organic solvent is potassium thiocyanate in aqueous methanol in the presence of acetic acid, and wherein said hydrocarbonsulfonyl chloride is methanesulfonyl chloride, said process comprising treating 6 Alpha ,7 Alpha -oxido-16-methylene-17 Alpha -acetoxy-4-pregnene-3,20-dione with potassium thiocyanate in aqueous methanol in the presence of acetic acid, and treating the thereby formed 6 Beta -thiocyanato-7 Alpha -hydroxy-16-methylene-17 Alpha -acetoxy-4-pregnene-3,20-dione with methanesulfonyl chloride in pyridine whereby is obtained 6-thiocyanato-16-methylene-17 Alpha -acetoxy-4,6-pregnadiene-3,20-dione.
 11. A process for preparing 6-thiocyanato-16-methylene-17 Alpha -lower alkanoyloxy-4,6-pregnadiene-3,20-diones of the following Formula I: 